Project Summary This project has two complementary goals: (1) to advance discovery of genes involved in substance use disorders using new multivariate genomic techniques, and (2) to characterize the risk associated with identified variants in diverse longitudinal samples in order to understand the spectrum of phenotypes associated with identified variants, across development, and in conjunction with the environment. Each of these areas represents critical steps in using genetic data to improve prevention, intervention, and treatment for substance use disorders (SUDs), and will lay the foundation as we move into an era of personalized medicine. Human gene identification efforts for substance use disorders lag behind other areas of psychiatry, in part due to constrained sample sizes of available SUD cases. However, recent meta-analyses of substance-related phenotypes such as age of initiation, consumption and problems, reveal significant genetic correlations across substance use outcomes, as well as with numerous other psychiatric and behavioral traits. These findings map onto twin data demonstrating significant genetic correlations across substance use disorders and other externalizing traits. This project will (Aim 1) apply new multivariate genetic methods to capitalize on genetic sharing between substance use phenotypes and related traits in order to boost power to detect common variants associated with substance use outcomes, and to characterize the latent pathways by which genetic variants operate. Bioinformatic characterization of these identified genetic variants will provide insight into underlying biological risk pathways, and phenotypic characterization of resultant polygenic risk scores will help us understand how risk unfolds across development and in conjunction with the environment. We will apply results from the multivariate analyses to two complementary longitudinal datasets, consisting of a population-based and high-risk sample, in order to (Aim 2a) map the behavioral phenotypes associated with the genetic risk scores identified in Aim 1 across adolescence and emerging adulthood; (Aim 2b) test for pathways of risk specific to sex and racial/ethnic background; and (Aim 2c) test for moderation of genetic risk by key environmental factors. Jointly, these analyses will advance our understanding of how genetic variation contributes to risk for substance use disorders.